title: Methamphetamine-induced occludin endocytosis is mediated by the Arp2/3 complex-regulated actin rearrangement.
abstract: Methamphetamine (METH) is a drug of abuse with neurotoxic and neuroinflammatory effects, which include disruption of the blood-brain barrier (BBB) and alterations of tight junction protein expression. This study focused on the actin cytoskeletal rearrangement as a modulator of METH-induced redistribution of tight junction protein occludin in brain endothelial cells. Exposure to METH resulted in a shift of occludin localization from plasma membranes to endosomes. These changes were accompanied by activation of the actin-related protein 2/3 (Arp2/3) complex, which stimulates actin polymerization by promoting actin nucleation. In addition, METH-induced coronin-1b phosphorylation diminishes the inhibitory effect of nonphosphorylated coronin-1b on actin nucleation. Blocking actin nucleation with CK-666, a specific inhibitor of the Arp2/3 complex, protected against METH-induced occludin internalization and increased transendothelial monocyte migration. Importantly, treatment with CK-666 attenuated a decrease in occludin levels in brain microvessels and BBB permeability of METH-injected mice. These findings indicate that actin cytoskeletal dynamics is detrimental to METH-induced BBB dysfunction by increasing internalization of occludin.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida 33136 and.
authors.forename: Minseon
authors.initials: M
authors.lastname: Park
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Brian
authors.initials: B
authors.lastname: Lim
authors.forename: Adam
authors.initials: A
authors.lastname: Wylegala
authors.forename: Michal
authors.initials: M
authors.lastname: Toborek
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000235:genetics / Q000378:metabolism*; D000199:Actins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D000697:Central Nervous System Stimulants / Q000009:adverse effects* / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects* / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008694:Methamphetamine / Q000009:adverse effects* / Q000494:pharmacology; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D062793:Occludin / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects / Q000235:genetics
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D000697:Central Nervous System Stimulants; D008840:Microfilament Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; C568987:Ocln protein, rat; C072061:coronin proteins; D008694:Methamphetamine
keywords: Actin; Arp2/3 Complex; Blood-Brain Barrier; Brain; Cytoskeleton; Endo; Endocytosis; Endothelium; Methamphetamine; Nucleation; Occludin; Tight Junctions